Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease

Individuals with progressive liver failure risk dying without liver transplantation. However, our understanding of why regenerative responses are disrupted in failing livers is limited. Here, we perform multiomic profiling of healthy and diseased human livers using bulk and single-nucleus RNA- and ATAC-seq. We report that in alcohol-associated liver disease, alterations in the hepatic immune milieu prevent hepatocytes from transitioning to proliferative progenitors. We also find differences in RNA binding protein expression, particularly of the ESRP, PTBP, and SR families, leading to misregulation of developmentally controlled RNA splicing. Our data pinpoint ESRP2 as a disease-sensitive splicing factor and support a causal role for its deficiency in the pathogenesis of severe alcoholic hepatitis. Notably, splicing defects in Tcf4 and Slk, two ESPR2 targets, alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways that are critical for normal liver regeneration. We further demonstrate that changes in stromal cell populations enrich failing livers with TGF-β, which suppresses the ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. Taken together, these findings indicate that misspliced RNAs are effective biomarkers for alcohol-associated liver disease, and targeting them could improve recovery in affected individuals.